Both Spanish league leaders were stunned Wednesday, with Barcelona losing 2-1 at last-place Leganes and Madrid falling 3-0 at Sevilla, marking the first time since 2015 that they lost on the same day.
The thrilling night also was marked by Pablo Fornals' beautiful goal from about 45 meters (50yards) away in Villarreal's 3-0 win at Athletic Bilbao, and by Valencia's winless streak being extended to seven matches after a draw against Celta Vigo.
Barcelona's loss came as Lionel Messi made his 700th appearance with the club, including 55 unofficial games. It was the second consecutive setback for the defending champions.
"We lost five points in three days," Barcelona coach Ernesto Valverde said. "It's difficult to explain."
The Spanish powerhouses have 13 points each after six rounds, two points in front of Atletico Madrid, which defeated Huesca 3-0 Tuesday for its second straight league win.
Real Madrid and Atletico play the city derby at Santiago Bernabeu Stadium on Saturday.
Alaves could join Barcelona and Real Madrid at the top of the standings if it wins its home match against Getafe on Thursday.
BARCELONA'S DEBACLE
Messi's celebration of his milestone match with the Catalan club was marred by a Leganes team which had only one point from its first five league games and was coming off three straight losses.
The club from Madrid's suburbs had never earned a point against Barcelona in its three seasons in the first division.
The 53rd-minute winner at Butarque Stadium was scored by Oscar Rodriguez, a former member of Real Madrid's youth teams who is on loan with Leganes. It came after a bad mistake by Barcelona defender Gerard Pique, who gave the ball away while trying to clear it from inside the area. Nabil El Zhar had scored the host's first goal a minute earlier to offset Philippe Coutinho's first-half opener for Barcelona, which has conceded seven goals in its first six matches.
Luis Suarez started the match on the bench and couldn't do much when he was brought on in the second half to try to reverse the team's disadvantage.
Messi has 58 fewer matches than Andres Iniesta with Barcelona. Xavi Hernandez holds the club record with 869 games.
MADRID'S FALL
Real Madrid entered the match at Sevilla with a chance to take sole possession of first place for the first time this season, but it didn't take long before it found itself in a deep hole.
Portugal forward Andre Silva scored in the 17th and 21st minutes to take his league-leading tally to six goals, and Wissam Ben Yedder added another in the 39th to leave Sevilla in control at the Ramon Sanchez-Pizjuan Stadium.
"It's simple, we gave it away in the first half," Madrid midfielder Casemiro said. "Then it was impossible to come back."
Luka Modric's goal early in the second half was called off after a video review showed he was offside.
Madrid's only previous setback in the league this season had been a draw at Athletic Bilbao in the fourth round.
Marcelo appeared to injure a muscle midway through the second half but coach Julen Lopetegui had already made all three substitutions.
Sevilla has won three in a row in all competitions, outscoring its opponents 14-3. It moved three points behind Madrid and Barcelona in the league.
"Sevilla was better and deserved to win," Lopetegui said. "We didn't start the way we wanted and paid for it by conceding two quick goals."
LONG-RANGE STRIKE
Fornals scored one of the goals of the season with his amazing strike in Villarreal's rout of Athletic.
After a clearance by Villarreal's defense in the 65th, Fornals picked up the loose ball a few meters in front of the mid-circle and fired it over Athletic goalkeeper Unai Simon, who couldn't get back in time to make a save.
The goal opened the scoring at San Mames Stadium and Villarreal went on to score twice again for its second win in three matches.
It was the first league loss for Athletic, which was coming off three straight draws.
VALENCIA'S MISERY
Valencia couldn't put an end to its early struggles, conceding late in a 1-1 home draw against Celta Vigo to remain winless.
Iago Aspas scored the equalizer in the 82nd minute at Mestalla Stadium after Michy Batshuayi had given the host the lead in the 25th.
The only other winless team in the league is promoted Valladolid, which hosts Levante on Thursday.
Valencia is yet to win in seven matches in all competitions this season.